Huge Undertaking - Goal: Ourselves

IOMMENT Potential areas of contention include ownership of the data and division of the scientific community into the 'haves' and the 'have nots'. For the HGM workshops the new political impetus will soon generate too much data to be handled efficiently by a biennial or even annual workshop. One solution is to attempt a continual update of the HGM workshop maps with periodic peer review at the workshops. This solution requires dedication from chromosome committees and the active participation of the rest of the interested community. The scientific changes derive from the introduction of new technologies for gene mapping and the need to combine information from many different sources. Future workshops and supporting databases will need to incorporate

short and long range restriction maps, maps of overlapping clones of contiguous DNA (contig maps) and some types of sequence information. Another pressing problem is the development of methods for combining mendelian maps based on different data sets. Until recently, the overall organization of the HGM workshops consisted only of passing a symbolic bell from one set of local organizers to the next. Responding to the increased size and costs of the workshops, as well as the need for long term planning, the most recent workshops have been guided by a standing executive committee. Within the framework of increased political interest in genome analysis and the need to coordinate the efforts of many different factions, nations and practi-

tioners of diverse technologies, it has been agreed that the HGM workshops should be overseen by the Human Genome Organization (HUGO). If all goes well this international body will discourage duplication of effort in the construction of genome maps, provide long term financial support for the HGM workshops and help ensure that the results of all genome research are freely available to all. In short, HUGO should promote order in the face of possible chaos.

References

1 Partridge, T.A. et al. (1989) Nature 337, 176-179 2 Rommens, J.M. el al. (1989) Science 245, 1059-1065 3 Riordan,J.R. et al. (1989) Science 245, 1066-1073 4 Kerem, B-S. etal. (1989) Science 245, 1073-1080

Huge Undertaking- G0al: Ourselves ALISONSTEWART EDITOR,TRENDSINGENETICS According to Daniel Koshland, editor of Science, the purpose of Human Genome 1 (2-4 October, San Diego) was to fulfil a duty of accountability, both to the public and to the scientific community, for the huge amounts of money and time that are to be spent on sequencing the human genome. Certainly, the proponents of the 'Human Genome Initiative' presented their case with almost missionary zeal, and the atmosphere of the meeting was one of great enthusiasm (detractors would no doubt say hype). Although many researchers in other areas of biology remain unconvinced that the human genome project will be funded by 'new' money, and claim that their research funds are already beginning to dry up, it does at least seem clear that many areas of genetic research will benefit from the project. Valuable information will come not only from the gene sequences themselves but also from the technology being developed to cope with the enormous magnitude of the mapping and sequencing task. New methods and approaches were a strong theme of the San Diego meeting,

though it wasn't always clear which ones have been mastered already or are definitely within reach, and which are still castles in the air. A variety of strategies will provide the markers on the genetic and physical maps of the genome that are to be completed within the first 10 years of the project's proposed 15-year lifetime. Those discussed at the meeting included the use of the polymerase chain reaction (PCR) for meiotic mapping of single sperm (N. Arnheim, University of Southern California), mapping by high resolution in situ hybridization (J. Lawrence, University of Massachusetts Medical Center), and radiation hybrid mapping (D. Cox, University of California, San Francisco). In the latter technique, hamster cell lines containing single human chromosomes are subjected to high levels of radiation, fragmenting the chromosomes. The fragments are rescued by making further somatic cell hybrids, with selection for those that have incorporated human chromosome material. Map construction depends on the principle that closely linked markers are less likely to be separated by TIG NOVEMBER1989 VOL. 5 XO. 11

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radiation damage than more distant ones. The many and varied mapping strategies that are in use generate different maps, and the problem is how to align them. Enter the latest addition to the human genome programme's lexicon: the STS (sequence tagged site). STSs are single copy sequences of 200-500 bp that could be retrieved by PCR. The idea is that STSs would be identified in marker DNA sequences defined by other mapping methods, and map information would then be stored in this 'common language'. C. Smith and C. Cantor (Lawrence Berkeley Laboratory) described how an STS map could be built up a b initio, by sequencing around rare-cutter sites and ordering the sites by hybridization. PCR-based strategies were much in evidence throughout the meeting, for example it was suggested that PCR could be used to link up markers, to close gaps between contigs and to traverse unclonable sequences. While in theory this is plausible, the present maximum range of PCR (less than 10 kb) places a limit on the number of

IOMMENT situations in which it can be applied in this way. The final five years of the human genome programme will see the bulk of the sequencing, using technology that is expected to improve many-fold during the 1990s. Sequencing (for labs lucky enough to have the necessary funds) has already entered the realms of advanced robotics, with minimal manual input: the current state-of-the-art, exemplified by L. Hood's lab (California Institute of Technology), with automated workstations and fluorescent detection of products, is a theoretical 36000 bp/person/week. The face of sequencing may even change completely if it proves possible to devise a method based on scanning tunnelling microscopy, which allows the bases to be 'seen' directly in single molecules of DNA. Two sessions of the meeting were devoted to discussing some of the benefits it is hoped that the human genome project will bring. There is no doubt that research on human genetic disease will gain immeasurably. Now that it has proved possible to find the genes associated with such diseases as Duchenne muscular dystrophy and cystic fibrosis, the pressure will be enormous for further disease genes to be identified (even though knowledge of the aberrant gene still leaves one very far from a cure). As R. Dulbecco (Salk Institute) pointed out, if the human genome project, by providing closely spaced markers covering the whole genome, can remove the need for the expensive and labourintensive approach that had to be used to find the CFgene (described by F. Collins, University of Michigan Medical Center), it may be cost-effective for that reason alone. T. Caskey (Baylor College of Medicine) described how, once disease genes have been found, DNA 'scanning' techniques can identify many of the different mutations found in affected individuals. Costs, organization and politics were the preoccupation of the last day of the meeting, when representatives from the USA (Cantor for the Department of Energy and J. Watson for the National Institutes of Health, NIH), European Community (P. Pearson) and Japan (N.

Shimizu) outlined their countries' plans for participation in the project. In the USA, the input of the Department of Energy (DOE) will be largely directed towards the three National Laboratories, each of which will first try its hand at mapping one of the smaller chromosomes and then graduate to a more challenging larger one. The clone libraries that will be built up will be freely available to interested research groups; this may allay some fears that the fruits of the genome project will be reserved for 'big science' and for commercial interests. NIH funding will be allocated mainly in the form of grants to research groups. Large collaborative projects are likely to be viewed most favourably. It was also made clear that the human genome will not be the only one in the limelight: those working on other 'fashionable' organisms (e.g.E. coli, yeast, Drosophila, mouse, C. elegans) can also hope to garner a few pennies from NIH's coffers. A compelling reason for this is that homology in different organisms is often the best way of identifying genes. This applies not only to single genes, but also to polygenic and quantitative traits. E. Lander (Whitehead Institute) described recent progress in mapping such traits in plants and in the mouse; from the mouse, it can often be just a short syntenic hop to humans. In addition, unlike humans, experimentally accessible and genetically well characterized organisms are invaluable for studying many aspects of gene expression and control. However, Watson warned that all genome sequencing proposals will come under rigorous scrutiny with regard to cost, and will therefore have the same imperative to improve technology. Don't bother to apply to NIH to sequence Your Favourite Organism if it's going to cost $10 a base; come back when you can show that you can do it for 1/20 of that cost. In Japan a number of agencies, both government and commercially funded, are involved in the human genome project. It was striking that only Japan appears to be systematically increasing investment not only in mapping and sequencing, but in setting up large research FI(, XOVEMBER1989 VOI.. 5 NO. 11 3(~-;

groups in areas that are most likely to benefit directly from the information emerging from the project, for example analysis of chromosome structure and behaviour. Japan's Human Frontier Science Program will finance workshops and fellowships to promote international exchange of information and training. Communication is also a theme of the programme in the (European Community) EC, which has to coordinate activities over 12 politically disparate countries. Current plans in member countries range from a substantial start-up budget available immediately (UK), to the more sceptical approach of the FRG, which has so far limited activities to setting up a planning con~mittee. Nevertheless, a joint EC working party exists, and other genome projects that are already underway include the complete sequencing of yeast chromosome 3, and a Drosophila mapping and sequencing project. All the organizations involved in the human genome project are stressing the importance of addressing the ethical and legal issues that will arise. They also emphasize the desirability of international cooperation and exchange of information; the best way to achieve this may be by joint funding of specific projects (an approach already being taken in a proposal to sequence the C. elegans genome). The international nature of the human genome initiative is also underlined by the setting up of HUGO, the Human Genome Organization. Initially financed by private medical research foundations, HUGO hopes eventually to attract multinational government funding. Although analysis of the human genome has been in progress for many years, the impetus given by the current large-scale injection of effort and money, and the public attention it has aroused, have given the 'Human Genome Initiative' the aura of a new undertaking. So when does the 15-year programme officially start? According to Watson, kick-off will be October 1990. No doubt hopes and expectations will be running high at Human Genome 2 in San Diego next September, with the starting whistle only a few weeks away.